SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF METHYL-SUBSTITUTED INDOLE [2,3-B] QUINOLINES - NOVEL CYTOTOXIC, DNA TOPOISOMERASE-II INHIBITORS

In furtherance of our SAR study on the chemistry and antitumor activit y of fused nitrogen heteroaromatic compounds, a series of linear, meth yl-substituted derivatives of 5H- and 6H-indolo[2,3-b]quinolines were synthesized according to the modified Graebe-Ullmann reaction. To esta blish the relationship between the physicochemical and biological acti vities of indole[2,3-b]quinolines, their lipophilic properties, cytoto xic and antimicrobial activity, and ability to induce topoisomerase II dependent pSP65 DNA cleavage in vitro were investigated. We found tha t the antimicrobial and cytotoxic activity of indolo[2,3-b]quinolines was strongly influenced by the position, and the number of methyl subs tituents and the presence of methyl group at pyridine nitrogen was ess ential for the cytotoxicity of these compounds. All indole[2,3-b]quino lines belonging to the 5H series, i.e., bearing a methyl group on the pyridine nitrogen, showed significant activity against procaryotic and eucaryotic organisms. They inhibited the growth of Gram-positive bact eria and pathogenic fungi at MIC range 3 x 10(-2) to 2.5 x 10(-1) mu m ol/mL, displayed cytotoxicity against KB cells ID50 in the range 2 x 1 0(-3) to 9 x 10(-3) mu mol/mL, and stimulated the formation of calf th ymus topoisomerase II mediated DNA cleavage at concentration between 0 .4 and 10 mu M. None of the indolo[2,3-b]quinolines belonging to the 6 H series, i.e., lacking a methyl group on the pyridine nitrogen, was a ctive in analogous tests. Of the investigated compounds, the most acti ve was 2,5,9,11-tetramethyl-5H-indolo-[2,3-b]quinoline, a compound bea ring the highest number of symmetrically distributed methyl groups. Th e interaction of indolo[2,3-b]quinolines with DNA was studied by measu ring the increase of calf thymus DNA denaturating temperature (T-m). T he Delta T-m values for the 5H series were found to be about 10 times as high as those for the 6H compounds. Indolo[2,3-b]quinolines with th e highest number of methyl groups had the greatest contribution to the increase in the T-m of calf thymus DNA. The values of Delta T-m reach ed 19 degrees C and 1.6 degrees C for the most substituted compounds o f both series.